Regulators of G-protein signaling (RGS) proteins are important modulators of signals initiated through G- protein coupled receptors (GPCRs). The action of RGS proteins is the acceleration of the deactivation of G- protein signals through modulation of G? subunit GTPase activity, which causes a termination of signal. While GPCRs have been classical drug targets, many cellular processes can be modulated by altering the action of RGS proteins. I propose to measure the interaction affinity of a variety of RGS proteins for their effector proteins (i.e. G?) using a novel high throughput flow cytometric method. With these parameters established, a library of diverse chemical compounds (~35,000) will be screened to identify modulators of RGS activity using the high throughput flow cytometric method. Once modulators are identified, complete quantitative structure-activity relationships will be evaluated and additional similar compounds will be characterized in both biochemical and cell-based assays. The use of these pharmacological modulators would provide utility for studying various disease in which RGS proteins could play a role, including Parkinson's disease (RGS9), Schizophrenia (RGS4), as well as cell proliferation and metastasis (LARG). [unreadable] [unreadable]